Innate Immunity Flashcards
Describe the innate defenses that guard against entry of microbes into body tissues
- Biochemical
- lactic and fatty acids in sweat and sebaceous secretions
- low pH on skin
- microbicidal factors in secreted fluids (tears, sweat, stomach acid, etc)
- Commensal organisms
- occupy body niches
- compete for nutrients
- produce inhibitory substances
- Mucus
- produced by membranes lining inner surfaces
- inhibits adherence of bacteria to epithelial cells
- Mechanical
- ciliary action, coughing, sneezing
- remove microbes caught in mucus
- flushing actions of urinating, crying, salivating
Distinguish the general characteristics and roles of neutrophils, aka polymorphonuclear leukocytes (PMNs), in innate immunity
- most abundant leukocyte in blood
- multilobed nucleus
- number increases drastically during infection and produced by bone marrow
- ingest microbes in circulation
- rapidly move into extravascular tissue at site of infection to ingest microbes
- lifespan of hours to 1-2 days
- early, short lived responders, but critical
Distinguish the general characteristics and roles of monocytes/macrophages in innate immunity
Monocytes -produced by bone marrow -circulate in blood -ingest microbes in blood and at sites of infection where they can differentiate into macrophages Macrophages -resides in tissues throughout the body -ingest and kill microbes, produce inflammatory cytokines, clear dead cells and initiate tissue repair -long life span
Describe the general mechanisms by which phagocytes (neutrophils and macrophages) clear microbes
- phagocytosis
- inflammation
- enhanced adaptive immunity
Explain the general characteristics and roles of dendritic cells
- produce cytokines
- promote inflammation and adaptive immune response
Explain the general characteristics and roles of mast cells in innate immunity
- contain cytoplasmic granules loaded with proteases (kill bacteria, inactivate toxins) and vasoactive amines (histamines) (vascular permeability)
- activated by microbes to degranulate and secrete prostaglandins and cytokines
Explain the general characteristics and roles of natural killer (NK) cells in innate immunity
- recognize infected or stressed cells
- kill targets by degranulating and releasing proteins that trigger apoptosis
- act in defense against intracellular pathogens (kill infected cells)
- act cooperatively with macrophages
- activate IL-12 produced by macrophages
- secrete interferon-y – activates macrophages
Describe the specific pathways of the complement system
Alternative Pathway
- triggered by activation of certain complement proteins on microbial surfaces
Lectin Pathway
-triggered by the binding of mannose-binding lectin to mannose residues on icrbial surface glycoproteins
-innnate immune defense
Classical Pathway
-triggered by antibodies to antigens
-antibody-mediated adaptive immunity
-can also be activated by proteins considered as innate defense proteins
Explain the principal sources and key functions of major cytokines, including tumor necrosis factor (TNF), interleukin(IL)-1, IL-6, IL-10, IL-12, interferon(IFN)-y and type I interferons (IFN-a and IFN-b) in innate immunity
- TNF: hypothalamus = induce fever; liver = acute phase proteins; main cytokine for recruiting neutrophils and monocytes to infection site
- IL-1: hypothalamus = induce fever; liver = acute phase proteins; main cytokine for recruiting neutrophils and monocytes to infection site
- IL-6: liver = acute phase proteins
- IL-10: macrophages, dendritic cells, T cells; inhibition of cytokine and chemokine production, reduced expression of costimulators & class II MHC molecules
- IL-12: dendritic cells and macrophages; IFN-y production, increased cytotoxic activity
- IL-y: NK cells, T lymphocytes; activation of macrophages, stimulation of some antibody responses
- IFN-a/b: plasmacytoid dendritic cells, virus infected cells; bind to receptors of infected cells or neighboring cells; activate signaling pathways that inhibit viral replication
What are specialized lymphocytes?
intraepithelial lymphocytes
What are defensins?
- antimicrobials against bacteria, fungi, and viruses
- small, cationic, cysteine-rich peptides
- produced by epithelial cells and leukocytes
Explain the concept and function of pathogen-associated molecular patterns (PAMPs) in innate immunity
- structures shared by many classes of microbes
- not present on human cells
- recognized by pattern recognition receptors (PRRs)
Explain the concept and function of damage-associated molecular patterns (DAMPs) in innate immunity
- various particles released by damaged or necrotic host cells
- not released by healthy cells
- recognized by certain receptors expressed by host cells
Explain the concept and function of pattern recognition receptors (PRRs) in innate immunity
- bind PAMPs and DAMPs
- expressed by phagocytes, dendritic cells, etc
- on cell surfaces, endosomes, cytosol
Describe the general features, cellular localization and functions of Toll-like receptors (TLRs)
- family of PRRs
- each has a ligand-binding domain and cytoplasmic signaling domain
- specific
- Cell surface TLR: for microbial proteins, lipids, and polysaccharides (components of extracellular microbes)
- Endosomal TLR: specific for nucleic acids not found in mammalian cells (intracellular microbes)
What does TLR-9 recognize?
CpG (C-G pairs)
What does TLR-3 recognize?
dsRNA – we don’t make that
Describe the general features and functions of NOD-like receptors (NLRs), the inflammasome and RIG-like receptors (RLRs)
NLR
-NOD1 and NOD2
-activate NFkB
NLRP3
- this + adaptor protein make inflamasome –> activate caspase 1 –> secrete IL-1B –> acute inflammation, fever
RLR – recognize viral RNA –> produce IFN
Compare and contrast the major receptors for innate and adaptive immunity in regard to specificity, expression and self/nonself discrimination
Specifity:
-I: specific to PAMPs
-A: specific to antigens, microbial and non-microbial
Expression:
-I: identical receptors on all cells, hundreds
-A: differentiated receptors, 2 types with millions of variations
Self/nonself deiscrimination:
-I: healthy host cells not recognized
-A: based on elimination/inactivation of self-reactive lymphocytes
Explain the general features and functions of the acute inflammatory response
Rolling:
-microbe enter subepithelial tissue
-microbe activates macrophages & dendritic cells
-production of TNF and IL-1 which stimulate expression of E-selectin by vascular endothelium
-blood leukocytes begin to bind thru selectin-ligand to E-selectin
Integrin Activation by Chemokines
-production of chemokines by activated innate defense cells and endothelial cells
-chemokines stimulate blood leukocytes
-increased affinity of leukocyte integrins
Stable Adhesion
-TNF & IL-1 stimulate expression of integrin ligands by endothelium
-stable binding of integrins to integrin ligands
-arrest of rolling leukocytes on endothelium
-re-organization of leukocyte cytoskeleton
Migration Through Epithelium
-chemokines and other chemoattractants stimulate leukocyte motility
-leukocytes migrate between endothelial cells
Examples of NLRs
NOD-1 & NOD-2
- activate NF-kB
-specific for bacterial peptidoglycan
NLRP-3
-specific for microbial products and DAMPs
-interacts with adaptor protein and caspase-1 to form inflammasome
-caspase-1 generates active IL-1B –> acute inflammation and fever
Examples of RLR
Cytosolic RNA sensors -recognize viral RNA -induce production of type I interferons Cytosolic DNA sensors -recognize microbial dsDNA -induce production of type I IFN Lectin receptors -cell surface; recognize carbohydrates -promote phagocytosis and inflammatory responses
What are the phagolysosome killing mechanisms?
- phagocyte oxidase –>reactive oxygen species(ROS)
- inducible nitric oxide synthase (iNOS) –> nitric oxide (NO)
- lysosomal proteases
What happens when reactive oxygen species (ROS) and nitric oxide (NO) are released by phagocytes?
- kill extracellular microbes (good)
- damage tissues (bad)
Difference between neutrophil and macrophage: origin
N: bone marrow
M: bone marrow in inflammatory reactions and some reside in tissues (stem cells in yolk salc of fetal liver)
Difference between neutrophil and macrophage: life span in tissues
N: 1-2 days
M: inflammatory - days or weeks; tissue residents - years
Difference between neutrophil and macrophage: responses to activating stimuli
N: rapid, short-lived enzymatic activity
M: more prolonged, slower, dependent on new gene transcription
Difference between neutrophil and macrophage: phagocytosis
N: rapid ingestion
M: prolonged ativity to ingest microbes, apoptotic cells, tissue debris, foreign material
Difference between neutrophil and macrophage: ROS
N: rapidly induced by assembly of phagocyte oxidase (respiratory burst)
M: less prominent
Difference between neutrophil and macrophage: NO
N: low levels - none
M: induced following transcriptional activation of iNOS
Difference between neutrophil and macrophage: degranulation
N: major response induced by cytoskeletal rearrangement
M: not prominent
Difference between neutrophil and macrophage: cytokine production
N: low levels per cell
M: major functional ability – requires transcriptional activation of cytokine genes
Difference between neutrophil and macrophage: Extracellular Traps
(nucleic acids spilling out of the cell and keeps microbes from leaving (pus))
N: rapidly induced
M: little
Difference between neutrophil and macrophage: secretion of lysosomal enzymes
N: prominent
M: less
What are mucosal associated variant T (MAIT) cells?
- in mucosal tissue, esp. liver
- innate defense against intestinal bacteria
What are gamma delta T cells?
- intraepithelial cell (IEL)
- recognize microbial lipids
What are NK-T cells?
- in epithelia and lymphoid organs
- recognize microbial lipids
What are B-1 cells?
- in peritoneal cavity and mucosal tissues
- produce antibodies in response to microbes and microbial toxins in gut
- produce “natural antibodies”
What are marginal zone B cells?
- edge of lymphoid follicles of spleen
- critical role in antibody responses to blood-borne polysaccharide-rich bacteria
Describe the general features and functions of the complement system in innate immunity
- many complement proteins act as proteases
- Plasma protein C3: central component; cleaved early in cascade (C3a and C3b)
- C3b acts as an opsonin and coats microbes –> facilitates phagocytosis
- C3a and C5a act as chemoattractants…promote leukoxyte recruitement (inflammation)
- microbial attack complex (MAC): microbial lysis
Describe the general function of the acute phase proteins in innate immunity and examples
- circulating levels of plasma proteins made by the liver rapidly increase after infection
- -mannose-binding lectin (MBL): binds mannose on microbial carbohydrates, aactivates complement cascade via lectin pathway, act as an opsonin (lectic receptor on phagocytes)
- -C-reactive protein (CRP): binds phosphorylcholine on microbes, act as opsonin (CRP receptor on macrophages), activates complement via classical pathway, common blood test to assess infection/inflammation
What are cytokines?
- soluble proteins that mediate immune and inflammatory reactions
- critical mediator of communication between the immune system and itself and with other cells
- typically secreted in small amounts and bind to high affinity receptors
- most act in autocrine or paracrine fashion, but can do endocrine signalingg in large quantities
What are interleukins?
molecularly defined cytokines
What are chemokines?
- family of structurally low -molecular weight cytokines
- stimulate leukocyte chemotaxis
- regulate leukocyte migration from blood into tissues by activating leukocyte integrins
- mediate spacial organization of immune cells with lymphoid organs
What happens when there are high levels of TNF?
- thrombus formation on endothelium
- lowered myocardial contractility + increased vasodilation & leakiness = lowered BP
What is sepsis?
- disseminated bacterial infection
- high levels of TNF, low BP, disseminated intravascular coagulation (DIC)
